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dc.contributor.authorZago-Schmitt, Matteoen
dc.date.accessioned2019-11-12T18:16:01Z
dc.date.available2019-11-12T18:16:01Z
dc.identifier.urihttp://hdl.handle.net/1974/27448
dc.description.abstractType 1 von Willebrand Disease (VWD) is an inherited bleeding disorder resulting from a quantitative deficiency in the procoagulant protein von Willebrand factor (VWF). Diagnosis is dependent on a reduction in VWF levels and the identification of an abnormal bleeding history. However, diagnosis and management of this condition are challenging due to the significant heterogeneity reported in bleeding symptoms and the absence of a correlation between circulating VWF levels and bleeding severity. The ability to increase VWF levels in response to hemostatic stress (i.e. vascular injury) is important in managing bleeding. To date, this ability, referred to as the hemostatic stress response, has not been prospectively evaluated as a disease modifier of the bleeding symptoms seen in Type 1 VWD. Desmopressin, used therapeutically, can also be used as a hemostatic stress surrogate, as can exercise, to study the response to injury. By performing desmopressin trials over two consecutive days, the response to repeated stress can be evaluated. The hemostatic stress response can also be characterized by studying subject-derived endothelial colony-forming cells (ECFCs). We aim to show that a decreased and less sustained rise in VWF in response to hemostatic stress surrogates contributes to a more severe bleeding phenotype in individuals with Type 1 VWD. This thesis demonstrated that Type 1 VWD individuals have a decreased and less sustained rise in VWF in response to hemostatic stress surrogates compared to controls. We demonstrated that the differences in VWF and FVIII levels between Type 1 VWD and control groups increases in response to desmopressin and that this increased difference was maintained for at least twenty-four hours. Further, Type 1 VWD participants exhibited indicators of increased clearance and decreased synthesis of VWF. Overall, we demonstrated that the decreased response is correlated with increased bleeding. ECFCs isolated from these participants were further characterized for VWF expression and secretion demonstrating that the hemostatic stress response may be modelled ex vivo. In conclusion, these data may be used to provide clinicians with a better understanding of the determinants of bleeding in Type 1 VWD and allow for better risk stratification in this patient population.en
dc.language.isoengen
dc.relation.ispartofseriesCanadian thesesen
dc.rightsQueen's University's Thesis/Dissertation Non-Exclusive License for Deposit to QSpace and Library and Archives Canadaen
dc.rightsProQuest PhD and Master's Theses International Dissemination Agreementen
dc.rightsIntellectual Property Guidelines at Queen's Universityen
dc.rightsCopying and Preserving Your Thesisen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectvon Willebrand Diseaseen
dc.subjectvon Willebrand Factoren
dc.subjectHemostatic stress responseen
dc.subjectHemostasisen
dc.subjectDesmopressinen
dc.subjectEndothelial colony-forming cellsen
dc.subjectBleeding Scoreen
dc.subjectBleedingen
dc.titleEvaluation of the hemostatic stress response in Type 1 von Willebrand Diseaseen
dc.typethesisen
dc.description.degreeM.Sc.en
dc.contributor.supervisorJames, Paulaen
dc.contributor.departmentPathology and Molecular Medicineen
dc.embargo.termsWe are requesting a restriction be put on this thesis as the data presented is part of an ongoing research project and has not yet been published. At the conclusion of this study we intend to publish this data.en
dc.embargo.liftdate2024-11-06T19:28:23Z
dc.degree.grantorQueen's University at Kingstonen


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